Allergic rhinitis, the most common atopic disease, has an estimated prevalence ranging from about 5 to about 22 percent of the general human population and is characterized by the symptoms of sneezing, nasal discharge, and nasal congestion. These symptoms are believed to be triggered by multiple mediators released from mast cells and other inflammatory cells. Current therapies, such as antihistamines, deal effectively with the sneezing and nasal discharge, but have little effect on congestion, which is a key symptom affecting the quality of life of patients.
Local allergen challenge in patients with allergic rhinitis, bronchial asthma, allergic conjunctivitis and atopic dermatitis has been shown to result in rapid elevation of prostaglandin D2 “(PGD2)” levels in nasal and bronchial lavage fluids, tears and skin chamber fluids. PGD2 has many inflammatory actions, such as increasing vascular permeability in the conjunctiva and skin, increasing nasal airway resistance, airway narrowing and eosinophil infiltration into the conjunctiva and trachea. PGD2 is the major cyclooxygenase product of arachidonic acid produced from mast cells on immunological challenge [Lewis, R A, Soter N A, Diamond P T, Austen K F, Oates J A, Roberts L J II, Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE, J. Immunol. 129, 1627-1631, 1982]. Activated mast cells, a major source of PGD2, are one of the key players in driving the allergic response in conditions such as asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis and other diseases [Brightling C E, Bradding P, Pavord I D, Wardlaw A J, New Insights into the role of the mast cell in asthma, Clin. Exp. Allergy 33, 550-556, 2003].
In the presence of sulfhydryl compounds, PGD2 is formed by the isomerization of PGH2, a common precursor of prostanoids, by catalytic action of prostaglandin D synthase “(PGDS)”. There are two isoforms of the PGDS enzyme: L-PGDS; and H-PGDS. H-PGDS is a cytosolic enzyme, which is distributed in the peripheral tissues, and which is localized in the antigen-presenting cells, mast cells, megakaryocytes, and Th2 lymphocytes. The action of the product PGD2 is mediated by G-protein coupled receptors: D prostaglandin “(DP)” and crTH2. See (1) Prostaglandin D Synthase: Structure and Function. T. Urade and O. Hayaishi, Vitamin and Hormones, 2000, 58, 89-120, (2) J. J. Murray, N. Engl. J. Med., 1986 Sep. 25; 315(13):800, and (3) Urade et. al, J. Immunology 168: 443-449, 2002.
Without wishing to be bound by theory, inhibiting the formation of PGD2 should have an effect on nasal congestion and, therefore, be of therapeutic benefit in allergic rhinitis. In addition, we believe that a PGDS inhibitor should be of therapeutic benefit in a number of other indications such as bronchial asthma, age-related macular degeneration (AMD) an/or or chronic obstructive pulmonary disease (COPD).
Age-related macular degeneration (AMD) is a degenerative and progressive ocular disease that results in loss of fine, central vision due to the degeneration of the macula. AMD is the most common cause of blindness in Europe and the United States for individuals over 50 years of age.
Chronic obstructive pulmonary disease (COPD) is a progressive, inflammatory disease that involves chronic bronchitis and emphysema. Symptoms include airflow limitation, excessive mucus production, coughing, reduced exercise capacity and reduced quality of life.
PGDS inhibitors have been reported. The compound, HQL-79, is reported to be a weak PGDS inhibitor, and is antiasthmatic in guinea pig and rat models (Matsusshita, et al., Jpn. J. Pharamcol. 78: 11, 1998). The compound Tranilast is described as a PGDS inhibitor. (Inhibitory Effect of Tranilast on Prostaglandin D Synthesase. K. Ikai, M. Jihara, K. Fujii, and Y. Urade. Biochemical Pharmacology, 1989, 28, 2773-2676). The following published patent applications also disclose PGDS inhibitors:
US2008/0207651A1 and US2008/0146569A1—pyridine and pyrimidine carboxamides;
JP2007-51121—pyrimidine carboxamides;
WO2007/007778—benzimidazole derivatives;
WO2008/122787—piperazine(thio)carboxamides; and
WO2005/094805—imine and amide derivatives.